A rare but life-threatening immune reaction in response to lamotrigine (Lamictal) requires prompt diagnosis and treatment, according to a recent alert from the U.S. Food and Drug Administration (FDA).

On April 25, the FDA issued what it calls a “drug safety communication” about the risk of a condition so rare that few neurologists have heard of it: hemophagocytic lymphohistiocytosis (HLH), a systematic immune reaction that can result in organ failure and death if not quickly treated.

Just eight such cases associated with lamotrigine, including one death, are known by the FDA to have occurred since the drug was first approved in 1994 as a treatment for epilepsy. Since then, it has also been approved for bipolar disorder, and is now increasingly prescribed off-label to treat anxiety, borderline personality disorder, treatment-resistant schizophrenia, and other psychiatric disorders.

In response to the alert, some immunologists criticized the FDA for focusing on HLH, for which diagnosis requires a bone marrow biopsy and treatment sometimes includes chemotherapy. They point out that the diagnostic criteria for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) overlaps with the criteria for HLH. In addition, both of the conditions often (but not always) involve a severe skin rash. DRESS is somewhat more common than HLH, they say, and is equally serious.

“Patients with DRESS have a lot of the same symptoms as with HLH,” said Kimberly A. Risma, MD, PhD, who studies both diseases as associate professor in the division of allergy and immunology at Cincinnati Children’s and the University of Cincinnati College of Medicine. “The treatment is exactly the same: You take away the lamotrigine and give high-dose steroids. A bone-marrow biopsy is totally unnecessary.”

Essentially, she and others who study DRESS and HLH told Neurology Today, neurologists who prescribe lamotrigine should be on the lookout for any rare case involving a severe, systemic immune reaction.

“These cases involve high fevers, anemia and liver function or hematologic abnormalities,” said Stephan Ladisch, MD, professor of pediatrics and biochemistry/molecular biology at George Washington University and a pioneering investigator into HMH since the 1970s. “This is not something mild. The severe sickness of the patient will cause the neurologist to perform an evaluation and make a referral.”

The FDA alert made a point of distinguishing between HLH and DRESS. It states: “Healthcare professionals should be aware that prompt recognition and early treatment is important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific. HLH may also be confused with other serious immune-related adverse reactions such as …DRESS.”

But in response to questions from Neurology Today, a spokesperson for the FDA stated in an email: “The FDA acknowledges that HLH and DRESS have overlapping features, including the finding of hemophagocytosis in some cases that fulfill the diagnostic criteria for DRESS, and diagnosis may be difficult. Our case series, however, included patients who met the diagnostic criteria for HLH, were diagnosed with HLH by their treating physicians, and received measures and treatments beyond high-dose corticosteroids and Lamictal discontinuation.”



The eight worldwide cases identified by the FDA include reports submitted directly to the agency through the FDA Adverse Event Reporting System (FAERS) as well as those found in the medical literature. They involved both children and adults, occurring within 24 hours after starting treatment with lamotrigine, and required hospitalization, medication and other treatments. Two cases occurred in the United States, while the other six occurred abroad.

The diagnostic criteria for HLH, last updated in 2004, requires that at least five of the following eight conditions be met: fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer-cell activity, hyperferritinemia, andoluble interleukin-2-receptor levels ≥ 2,400 U/mL.

Although not included among the eight criteria, skin involvement occurs in about two-thirds of cases, ranging from erythroderma to pupuric macules, papules, and morbilliform eruptions. Symptoms can also include swollen lymph nodes, yellow skin or eyes, unusual bleeding or nervous system disturbances, the FDA noted.

Three of the eight cases identified by the FDA fulfilled only four of the criteria for diagnosing HLH, but the others fulfilled the necessary five. According to the alert: “The eight cases had signs and symptoms including fever (n=8), thrombocytopenia (n=8), hyperferritinemia (n=8), hypofibrinogenemia (n=5), splenomegaly (n=3), anemia (n=3), hypertriglyceridemia (n=2), low or absent natural killer (NK) cells (n=1), and neutropenia (n=1). All eight cases had positive bone marrow biopsies consistent with hemophagocytosis.”

Doses of lamotrigine ranged widely, from as little as 25 mg every other day to 250 mg once daily. Treatment included steroids in six of the eight patients, intravenous immunoglobulin in four, blood products in two, and chemotherapy in two.

In addition to releasing the alert, the FDA is requiring that a new warning about the risk of HLH be added to the prescribing information on the drug labels for lamotrigine.



One of the few case reports of lamotrigine-associate HLH in an adult was published last year as a letter to the editor in the American Journal of Therapeutics.

The letter describes a 26-year-old man with a medical history of anxiety and paranoia who had been stable for three years on benzatropine and risperidone. Three months before presenting to the emergency department at Baystate Medical Center in Springfield, MA, he had been started on lamotrigine as a mood stabilizer by his psychiatrist. His symptoms included generalized malaise, fever, fatigue, and bruising for the prior six weeks.

“Laboratory work showed new severe pancytopenia with white blood cell count 0.9, hemoglobin of 5.5, and platelet count of 65,000,” the letter stated. “In addition, he had elevated liver function test with bilirubin of 1.6, aspartate dehydrogenase of 834, international normalized ratio of 2.53, fibrinogen <60, and elevated ferritin of 44,472.”

Based on those findings, a bone marrow biopsy was performed, showing elevated histiocytes with erythrophagocytosis, pure red-cell aplasia and abnormal lympohistiocytic infiltrate. The patient was initially treated with fluids, irradiated leuko-depleted packed red blood cells, and irradiated leuko-depleted platelets. After the diagnosis of HLH had been made, he was treated with the chemotherapy drug etoposide, and with the corticosteroid dexamethasone. He recovered and was discharged home. ​​



The distinction between DRESS and HLH is blurred somewhat by the rarity of both diseases and the fact that HLH was first recognized in the 1970s by hematologists and oncologists, who are still the primary specialty who treat it. DRESS, on the other hand, can also be treated by immunologists.

“With HLH, you almost always have cytopenia, which can mean you have cancer,” said Michael B. Jordan, MD, a hematologist/oncologist and associate professor of pediatrics at Cincinnati Children’s and the University of Cincinnati College of Medicine. “That’s why historically hematologists have gotten involved.”

HLH comes in two forms: primary, due to a genetic abnormality that can be cured only with a stem cell transplantation, or secondary, which occurs as a reaction to certain medications, tumors or infections.

“A hematologist or oncologist would be most likely to recognize HLH,” said Dr. Ladisch, who practices in those very fields. “I wouldn’t confuse it with DRESS. If you look in bone marrow in HLH, you don’t see high levels of eosinophilia, as you will with DRESS.”

But according to published diagnostic criteria for DRESS, eosinophilia is neither necessary nor sufficient to diagnose it. Other criteria include fever, enlarged lymph nodes, atypical lymphocytes, skin rash, and internal organ involvement.

Dr. Jordan offered a slightly different perspective on the distinction between the two diseases. “I would say that DRESS is a less severe form of HLH,” he said. “As it gets more severe, it becomes more obviously HLH-like in nature.”

He agreed with Dr. Risma, however, that distinguishing between the two may not be necessary, since treatment is the same either way, at least when it occurs as a reaction to lamotrigine.

“Just because somebody does a bone marrow biopsy and finds hemophagocytosis doesn’t mean you need to treat them with chemotherapy,” she said. “You can get secondary HLH for a lot of reasons, and we don’t necessarily treat them all with chemotherapy. The danger here is treating them with too much medicine instead of just steroids and withdrawing the medication.”

Other severe immune reactions to lamotrigine can include Stevens-Johnson syndrome, pseudolymphomas, lymphadenopathy, limbic encephalitis, and a lupus-like syndrome.

But a measure of just how rare any of these conditions can be seen in the experience of Nathan Fountain, MD, professor of neurology and director of the F.E. Dreifuss Comprehensive Epilepsy Program at the University of Virginia School of Medicine. Before reading the FDA notice, he said, he had never seen nor heard of HLH.

“DRESS is something we do recognize as a rare reaction to lamotrigine,” he said. “Most neurologists who treat epilepsy have seen or heard of it.”

But even when it comes to Stevens-Johnson and other severe rashes caused by lamotrigine, Dr. Fountain said, “over the years we have learned that if you start at a low dose, it’s much less likely. As a result, although you have to take a severe rash very seriously, it is now very uncommon.”

A 2015 meta-analysis and post-marketing cohort analysis done in ChNA, published in the journal Seizure, found that the overall incidence of skin rash with lamotrigine therapy ranged from 9.98 percent in prospective studies, to 7.19 percent in retrospective studies, to 2.09 percent in post-marketing reports. Another 2015 paper by the same first author found 57 cases of DRESS associated with the drug. Two of the patients died and one needed a liver transplant.



FDA safety alert: https://www.fda.gov/Drugs/DrugSafety/ucm605470.htm
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Our Source: Article By D. Hurley for  Neurology Today